Project Summary: There is a rapidly growing body of evidence that Mller glia can are a source of retinal progenitors to promote neural regeneration. Many studies have demonstrated that Mller glia can become proliferating progenitor cells in the retinas of different vertebrate species. Most reports have studied Mller glia-derived progenitors in acutely damaged retinas. However, little is known about the mechanisms that stimulate neurogenesis from Mller glia-derived progenitors in undamaged retinas or retinas undergoing slow, progressive degeneration. Furthermore, the regeneration of retinal neurons in warm-blooded vertebrates is limited compared to that seen in cold-blooded vertebrates. Therefore, the identification of the secreted factors and signaling pathways that permit and/or stimulate neural regeneration from Mller glia-derived progenitors is crucially important to developing new therapies to treat degenerative diseases of the human retina. We have obtained compelling novel preliminary data indicating that cell-signaling through the nuclear factor kappa-light- chain-enhancer of activated B cells (NF?B) and the activity of Enhancer of Zeste Homolog 2 (EZH2) impacts the de-differentation and reprogramming of Mller glia into proliferating, neurogenic retinal progenitors. We will investigate how the phenotype and plasticity of the Mller glia are regulated by NF?B and EZH2 in normal, damaged and growth factor-treated retinas. We will use a combination of pharmacological and genetic approaches to selectively activate or inhibit NF?B and EZH2 in Mller glia. We will compare and contrast how NF?B-signaling and EZH2-acitvity impact the formation of Mller glia-derived progenitors in chick and rodent model systems with different inherent capacities for retinal regeneration. We expect that the completion of the experiments described in this proposal will provide significant new information regarding how NF?B and EZH2 influence mature Mller glia, the formation of Mller glia-derived progenitors and regeneration of retinal neurons. Identification and understanding of the mechanisms that enhance the neurogenic potential of Mller glia is required to develop new therapies for sight-threatening diseases, such as glaucoma and macular degeneration that involve the loss of retinal neurons.